Since the beginning of this project we have screened over 1200 subjects for this study. We have enrolled approximately 150 youth with bipolar disorder (BD), 180 subjects at risk for BD because they have a parent or sibling with the illness, 200 control subjects, and 75 adults with BD. This year, approximately 75 new subjects were enrolled. This year we continued our work identifying potential biomarkers in youth with bipolar disorder;understanding their pathophysiology;comparing these biomarkers in adults vs. children with bipolar disorder;and identifying the extent to which these biomarkers index risk for the illness. Previous work on this project identified deficits in face emotion identification and in response flexibility in youth with bipolar disorder, as well as in youth at familial risk for the illness because of a parent or a sibling with the illness. This year, we extended our work identifying the extent to which these deficits are specific to bipolar disorder, and studying the neural mediators of these deficits. With regard to response flexibility, we published work indicating that children with a number of different psychiatric illnesses, including bipolar disorder and depression, have deficits on response reversal tasks. However, fMRI work being prepared for publication indicates that the neural circuitry mediating these deficits differs between those with bipolar disorder and those with severe, non-episodic irritability. Similarly, both youth with bipolar disorder and those with severe irritability exhibit deficits on face emotion labeling tasks. However, work published this year, as well as additional studies under review or being prepared for publication, indicate that the neural circuitry mediating face emotion labeling deficits differs between these two groups. For example, data published this year identifies how amygdala dysfunction differs among youth with BD, those with severe irritability and hyperarousal symptoms (severe mood dysregulation or SMD, see MH002786-07), those with attention deficit hyperactivity disorder (ADHD), and controls. These data are important because of a school of thought in the child psychiatry community suggesting that bipolar disorder presents in children, not with episodes of mania and depression (as in adults), but instead with severe, non-episodic irritability. Work published this year, or being prepared for publication, adds to a growing number of studies indicating clinical, longitudinal, and neural differences between these two populations. In addition, these studies indicate how brain-based measures can be used to differentiate clinical groups, and ultimately point toward a future time when diagnosis in psychiatry will use such measures in addition to clinical assessment. Our work in children at risk for bipolar disorder continues. Last year, the program was extended to include, not only school aged children at risk for BD, but also preschool children. This expansion required the development of neurocognitive and affective tasks that could be used in samples ranging in age from preschool through adulthood. Preliminary data from observational studies suggest that at risk preschoolers may differ from age-matched controls in having difficulty regulating negative emotions. This sample is being expanded. We embarked on several new collaborations with molecular geneticists this year. One allowed to examine amygdala activity, as measured during a face processing task, in association with a genome wide association scan. This study found an association between amygdala activity and DOK 5, which encodes a substrate of tropomyosin-related kinase B/C receptors involved in neurotrophin signaling. This SNP accounted for about 33% of the variance in youths with BD and 12% of the variance in healthy youths. In addition, we are involved in a consortium examining copy number variants in bipolar disorder and other psychiatric illnesses. One paper published this year found an association between bipolar disorder and microduplications of a 600-kb genomic region of chromosome 16p11.2. Finally, in collaboratoin with an intramural molecular geneticist, we are beginning a study in the genetically informative Amish population. Our role will be to clinically assess offspring of bipolar adults in this population, as well as to obtain behavioral measures that we have found to be aberrant in non-Amish youth at risk for bipolar disorder. We also intend to follow these children longitudinally to determine associations between genetic markers and performance on behavioral tasks, on the one hand, and genotype on the other. We have continued to recruit for a double-blind, placebo-controlled trial of riluzole in children with BD and severe comorbid anxiety. To be eligible for this trial, children must have failed at least two courses of standard treatment. Withdrawal from their current medication regimen occurs on an inpatient unit at the NIH Clinical Center. Once treatment with riluzole or placebo has begun, patients can continue the trial in the day treatment center (if they live locally) or at home, depending on their clinical status. In conjunction with their stay on the inpatient unit, patients can choose to participate in a study involving sleep manipulation. This study combines sleep extension and restriction with neuroimaging. The study is designed to yield information about the pathophysiology underlying the association between sleep deprivation and change in mood state in patients with bipolar disorder, and hence about the mechanisms mediating mood change in patients with bipolar disorder.